Michael Arnold, DO, FAAFP

Managing chronic obstructive pulmonary disease (COPD) presents a significant challenge to busy clinicians in many ways, especially when one is approaching the long list of inhaled pharmaceutical agents with an eye toward a cost-effective, patient-centered regimen. Inhaled agents remain expensive, with few available in generic form.

Our primary goal in this article is to detail these agents’ utility, limitations, and relative cost. Specifically, we review why the following considerations are important:

• Choose the right delivery device and drug while considering patient factors.
• Provide patient education through allied health professionals.
• Reduce environmental exposures.
• Rethink the use of inhaled corticosteroids (ICS).
• Understand the role of dual therapy and triple therapy.

Guidelines recommend reassessing inhaler technique at every visit and when evaluating treatment response.

There are numerous other treatment modalities for COPD that are recommended in national and international practice guidelines, including vaccination, pulmonary rehabilitation, home visits, phosphodiesterase-4 inhibitors, oral glucocorticoids, supplemental oxygen, and ventilatory support.¹ Discussion of those modalities is beyond the scope of this review.

Pathophysiology and pharmacotherapy targets

COPD is characterized by persistent respiratory symptoms and airflow limitation, usually due to airway or alveolar abnormalities, or both, caused by environmental and host factors.² Sustained lung parenchymal irritation results from exposure to noxious fumes generated by tobacco, pollution, chemicals, and cleaning agents. Host factors include lung immaturity at birth; genetic mutations, such as alpha-1 antitrypsin deficiency and dysregulation of elastase; and increased reactivity of bronchial smooth muscles, similar to what is seen in asthma.¹

IMAGE: © JOE GORMAN

Improving ventilation with the intention of relieving dyspnea is the goal of inhaler pharmacotherapy; targets include muscarinic receptors and beta 2-adrenergic receptors that act on bronchial smooth muscle and the autonomic nervous system. Immune modulators, such as corticosteroids, help reduce inflammation around airways.¹ Recent pharmacotherapeutic developments include combinations of inhaled medications and expanding options for devices that deliver drugs.

Delivery devices: Options and optimizing their use

Three principal types of inhaler devices are available: pressurized metered-dose inhalers (MDIs), dry-powder inhalers (DPIs), and soft-mist inhalers (SMIs). These devices, and nebulizers, facilitate medication delivery into the lungs (TABLE 1^3-9).

Errors in using inhalers affect outcome. Correct inhaler technique is essential for optimal delivery of inhaled medications. Errors in technique when using an inhaled delivery device lead to inadequate drug delivery and are associated with poor outcomes: 90% of patients make errors that are classified as critical (ie, those that reduce drug delivery) or noncritical.² Critical inhaler errors increase the risk of hospitalization and emergency department visits, and can necessitate a course of oral corticosteroids.¹⁰ Many critical errors are device specific; several such errors are described in TABLE 1.^3-9

Continue to: Patient education

Patient education is necessary to ensure that drug is delivered to the patient consistently, with the same expectation of effect seen in efficacy studies (which usually provide rigorous inhaler technique training and require demonstration of proficiency).^1,2,10 For the busy clinician, a multidisciplinary approach, discussed shortly, can help. Guidelines developed by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommend that inhaler technique be reassessed at every visit and when evaluating treatment response.¹TABLE 1^3-9 provides information on each device type, patient requirements for use, proper technique, common errors in use, and tips for optimizing delivery.

Inhaler education and assessment of technique that is provided to patients in collaboration with a clinical pharmacist, nursing staff, and a respiratory therapist can help alleviate the pressure on a time-constrained primary care physician. Furthermore, pharmacist involvement in the COPD management team meaningfully improves inhaler technique and medication adherence.^6,7 Intervention by a pharmacist correlates with a significant reduction in number of exacerbations; an increased likelihood that the patient has a COPD care plan and has received the pneumococcal vaccine; and an improvement in the mean health-related quality of life.^11,12

In primary care practices that lack robust multidisciplinary resources, we recommend utilizing virtual resources, such as educational videos, to allow face-to-face or virtual education. A free source of such resources is the COPD Foundation,^a a not-for-profit organization funded partly by industry.

Short- and long-acting inhaled medications for COPD

Each class of inhaled medication for treating COPD is discussed broadly in the following sections. TABLE 2¹ provides details about individual drugs, devices available to deliver them, and starting dosages.

Short-acting agents

These drugs are available in MDI, SMI, and nebulizer delivery devices. When portability and equipment burden are important to the patient, we recommend an MDI over a nebulizer; an MDI is as efficacious as a nebulizer in improving forced expiratory volume in 1 second (FEV₁) and reducing the length of hospital stay for exacerbations.⁴

Continue to: SABAs

Short-acting beta 2-adrenergic agonists (or beta-agonists [SABAs]). Beta-­agonists are typically used to treat exacerbations. They facilitate bronchodilation by upregulating cyclic adenosine monophosphate, preventing smooth-muscle contraction, and reducing dynamic hyperinflation. The effect of a SABA lasts 4 to 6 hours.

In general, SABAs are not recommended for daily use in stable COPD. However, they can be useful, and appropriate, for treating occasional dyspnea and can confer additional symptom improvement when used occasionally along with a long-acting beta 2-adrenergic agonist (or beta-agonist [LABA]; discussed later).¹

Continue use of a long-acting bronchodilator during exacerbations, when feasible.

Albuterol, a commonly used SABA, is less expensive than, and just as effective as, same-class levalbuterol for decreasing breathlessness associated with acute exacerbations. There is no significant difference between the 2 drugs in regard to the incidence of tachycardia or palpitations in patients with cardiovascular disease.¹³

Although no significant differences have been observed in outcomes when a nebulizer or an MDI is used to administer a SABA, it’s wise to avoid continuous SABA nebulizer therapy, due to the increased risk of disease transmission through the generation of droplets.^1,4 Instead, it’s appropriate to use an MDI regimen of 1 to 3 puffs every hour for 2 to 3 hours, followed by 1 to 3 puffs every 2 to 4 hours thereafter, based on the patient’s response.^1,4

Short-acting muscarinic antagonists (SAMAs). Muscarinic antagonists achieve bronchodilation by blocking acetylcholine on muscarinic receptors. We do not specifically recommend SAMAs over SABAs for treating COPD exacerbations in our patients: There is no difference in improvement in FEV₁ during an acute exacerbation. Nebulized delivery of a SAMA raises concern for an increase in the risk of acute narrow-angle glaucoma, a risk that can be reduced by using a mask during administration.^1,14

Continue to: SABA + SAMA

SABA + SAMA. One combination formulation of the 2 short-term classes of drugs (albuterol [SABA] + ipratropium [SAMA]), US Food and Drug Administration (FDA)–­approved for every-6-hour dosing, is available for SMI delivery devices and nebulizers. In the setting of a hospitalized patient who requires more frequent bronchodilator dosing, we use albuterol and ipratropium delivered separately (ie, dosed independently), with ipratropium dosed no more frequently than every 4 hours.

Long-acting agents

The mechanisms of long-acting agents are similar to those of their short-acting counterparts. The recommendation is to continue use of a long-acting bronchodilator during exacerbations, when feasible.¹

LABA monotherapy reduces exacerbations that result in hospitalization (number needed to treat [NNT] = 39, to prevent 1 hospitalization in an 8-month period).¹⁵ Specifically, formoterol at higher dosages reduces exacerbations requiring hospitalization (NNT = 23, to prevent 1 exacerbation in a 6-month to 3-year period).¹⁵ Evidence supports better control of symptoms when a LABA is combined with a long-acting muscarinic antagonist (LAMA; discussed shortly).^1,15

Adverse effects of LABAs include sinus tachycardia, tachyphylaxis, somatic tremors, and, less commonly, hypokalemia—the latter specific to the LABA dosage and concomitant use of a thiazide diuretic. Other adverse effects include a mild decrease in the partial pressure of O₂ and, in patients with heart failure, increased oxygen consumption. Although higher dosages are not associated with an increased incidence of nonfatal adverse events, there appears to be no additional benefit to higher dosages in regard to mortality, particularly in patients with stable COPD.^1,15

LAMA. Monotherapy with a LAMA reduces the severity of COPD symptoms and reduces the risk of exacerbations and hospitalization (NNT = 58, to prevent 1 hospitalization in a 3 to 48–month period).¹⁶ Tiotropium is superior to LABA as monotherapy in (1) reducing exacerbations (NNT = 33, to prevent 1 exacerbation in a 3 to 12–month period) and (2) being associated with a lower rate of all adverse events.¹⁷ LAMAs also confer additional benefit when used in combination with agents of other classes, which we discuss in a bit.

Continue to: The most commonly...

The most commonly reported adverse effect of a LAMA is dry mouth. Some patients report developing a bitter metallic taste in the mouth.¹

ICSs are not recommended as monotherapy in COPD.¹ However, an ICS can be combined with a LABA to reduce the risk of exacerbations in patients with severe COPD (NNT = 22, to prevent 1 exacerbation per year).¹⁸ However, this combination increases the risk of pneumonia in this population (number needed to harm [NNH] = 36, to cause 1 case of nonfatal pneumonia per year).¹⁸

ICSs increase the incidence of oropharyngeal candidiasis and hoarseness. In addition, ICSs increase the risk of pneumonia in some patients with COPD¹⁸—in particular, current smokers, patients ≥ 55 years of age, and patients with a history of pneumonia or exacerbations, a body mass index < 25, or severe COPD symptoms.^1,18 ICS therapy does reduce the risk of COPD exacerbations in patients with a history of asthma or with eosinophilia > 300 cells/μL and in those who have a history of hospitalization for COPD exacerbations.^19,20

When portability and equipment burden are important to the patient, consider a metereddose inhaler (MDI) over a nebulizer: An MDI is equally efficacious.

The risk of pneumonia is not equal across all ICS agents. Fluticasone increases the risk of pneumonia (NNH = 23, to cause 1 case of pneumonia in a 22-month period).²¹ Budesonide showed no statistically significant increase in risk of pneumonia.²² However, further studies on the risk of pneumonia with budesonide are needed because those cited in the Cochrane review²¹ were much smaller trials, compared to trials of fluticasone, and of low-to-moderate quality. Furthermore, evidence is mixed whether ICS monotherapy in COPD worsens mortality during an 18-month study period.^21-23

For these reasons, it’s reasonable to (1) exercise caution when considering the addition of an ICS to LABA therapy and (2) limit such a combination to the setting of severe disease (as discussed already).

Continue to: LABA + LAMA

LABA + LAMA. In a trial of patients with moderate-to-severe COPD, combining a LABA and a LAMA did not reduce the risk of exacerbations or hospitalizations, compared to LABA or LAMA monotherapy, but did improve subjects’ reported daily symptoms and quality of life scores (using the St. George’s Respiratory Questionnaire^b; NNT = 14 [LAMA monotherapy] and NNT = 9 [LABA monotherapy], both in a 3 to 12–month period).²⁴ However, another study that looked at patients with moderate-to-severe COPD found that combining a LABA and a LAMA led to fewer exacerbations (NNT = 22, to prevent 1 exacerbation in a 3 to 12–month period) and a lower risk of pneumonia (NNT = 93, to prevent 1 case of pneumonia in a 3 to 12–month period) than LABA + ICS.²⁵

LABA + ICS. This dual therapy is falling out of favor, compared to treatment with LABA + LAMA, because LABA + ICS formulations are less effective at reducing exacerbations and increase the risk of pneumonia in patients with moderate-to-severe COPD.^1,25 However, LABA + ICS therapy still has a role in a subset of patients with COPD (discussed in the section on ICS). A LABA combined with an ICS does reduce exacerbations in patients with severe COPD (NNT = 22, to prevent 1 exacerbation per year).¹⁸ Expect that the reported rates of candidiasis, hoarseness, and pneumonia associated with an ICS will be similar with LABA + ICS.¹⁸

LABA + LAMA + ICS. These are the newest combination inhaled agents approved for clinical use. It is recommended that escalation to such triple therapy be reserved for patients with persistent dyspnea on LAMA + LABA therapy and who have the factors (previously described) that suggest benefit from adding an ICS.¹ Several clinical trials have provided guidance:

• In the 2018 TRIBUTE trial,²⁶ beclometasone (ICS) + formoterol (LABA) + glycopyrronium (LAMA) ^c outperformed indacaterol (LABA) + glycopyrronium for preventing moderate-to-severe exacerbations (NNT = 11, to prevent 1 exacerbation per year) in patients with symptomatic COPD who have severe or very severe airflow resistance and a history of a moderate-to-severe exacerbation during the previous year.
• In the 2017 TRINITY trial,²⁷ beclometasone + formoterol + glycopyrronium^c outperformed tiotropium (LAMA) in preventing moderate-to-severe exacerbations (NNT = 9, to prevent 1 exacerbation per year) in patients with an FEV₁ < 50% and a history of ≥ 1 moderate-to-severe exacerbation during the previous year.
• In the 2020 ETHOS trial,²⁸ budesonide + formoterol + glycopyrronium (approved by the FDA in 2020 under the brand name Breztri) outperformed both glycopyrrolate + formoterol (LABA) and budesonide (ICS) + formoterol in preventing moderate-to-severe exacerbations (NNT = 56 and 34, respectively, to prevent 1 exacerbation per year) in patients with moderate-to-severe COPD who had a history of ≥ 1 exacerbation in the previous year. Additionally, higher-dose budesonide + formoterol + glycopyrronium reduced 1-year mortality to a modest degree compared to glycopyrrolate + formoterol (NNT = 100, to prevent 1 death in a 12-month period).
• A 2016 Cochrane review that compared tiotropium + LABA + ICS to tiotropium monotherapy²⁹ showed improvement in FEV₁ and patient-reported symptoms and quality of life scores. However, the review showed no difference in exacerbations or hospitalizations over a 1-year period.

Mitigating environmental exposures that affect inhaler medication efficacy

Tobacco smoke. Emphasizing smoking cessation is highly relevant in patients who are still smoking. Smoking impedes the efficacy of ICSs in reducing exacerbations of COPD.³⁰ Along with improved lung function, former smokers with COPD experience fewer exacerbations (NNT = 73, to prevent 1 exacerbation in a 4-year period for all former smokers; NNT = 33, to do so for smokers who quit > 10 years ago).^31,32

The continuous use of shortacting betaagonist nebulizer therapy can increase the risk of disease transmission through the generation of droplets.

A 2005 Veterans Health Administration study showed reduced mortality in smokers who were enrolled in a 10-week smoking cessation program, had access to nicotine replacement therapy, and received strong physician messaging.³³ Despite a 20% to 25% quit rate, the NNT was 56 to prevent 1 death in 14.5 years across the entire group. It is worth having patients take advantage of this 3-pronged approach if it is available in your community or health system.

Continue to: Exposure to air pollution

Exposure to air pollution. Air pollutants other than tobacco smoke remain important modifiable factors that impact COPD. These include organic and inorganic dusts, chemical agents and fumes, and burning of solid biomass (eg, wood, coal) indoors in open fires or poorly functioning stoves.¹ With this risk in mind, counsel patients regarding efficient home ventilation, use of nonpolluting cooking stoves, and the reduction of occupational exposure to these potential irritants.

GOLD approach to starting and adjusting inhaled therapy

Initiating inhaled therapy

A good resource for family physicians is the GOLD refined ABCD assessment scheme for initiating inhaler therapy that integrates symptoms and exacerbations (TABLE 3¹). To assess the severity of dyspnea, either the Modified Medical Research Council (mMRC) Questionnaire or COPD Assessment Test (CAT) can be used. A moderate exacerbation requires an oral corticosteroid or antibiotic, or both; a severe exacerbation requires an emergency department visit or hospitalization, or both. TABLE 3¹ offers a guide to choosing initial therapy based on these factors.¹

Following up on and adjusting an inhaler regimen

Adjust inhaler pharmacotherapy based on whether exacerbations or daily symptoms of dyspnea are more bothersome to the patient. Escalation of therapy involves adding other long-acting agents and is warranted for patients with exacerbations or severe or worsening dyspnea. Before escalating therapy with additional agents, reassess the appropriateness of the delivery device that the patient has been using and assess their adherence to the prescribed regimen.¹

Dyspnea predominates. Escalate with LABA + LAMA. For a patient already taking an ICS, consider removing that ICS if the original indication was inappropriate, no response to treatment has been noted, or pneumonia develops.¹

Exacerbations predominate. Escalate with LABA + LAMA or with LABA + ICS. Consider adding an ICS in patients who have a history of asthma, eosinophilia > 300 cells/uL, or eosinophilia > 100 cells/uL and 2 moderate exacerbations or 1 severe (ie, hospitalizing) exacerbation. This addition of an ICS results in dual or triple therapy (ie, either LABA + ICS or LABA + LAMA + ICS).¹

Continue to: Unclear what predominates?

Unclear what predominates? Follow the exacerbation predominance pathway.¹

Additional decision-making might be necessary in several circumstances:

• For the patient who requires further titration beyond these pathways, consider triple therapy as LABA + LAMA + ICS, unless the eosinophil count is < 100 cell/μL.¹
• Consider de-escalating ICS therapy if the patient develops pneumonia, there is a lack of demonstrated benefit, or the initial indication was uncertain or inappropriate.
• For the patient who continues to have significant dyspnea despite dual or triple therapy, consider investigating and treating other causes of dyspnea.¹

Last, keep in mind that evidence is limited regarding escalating the dosage of these agents (1) beyond what is listed in TABLE 2¹ and (2) in specific instances mentioned in the discussion of each inhaler class.

^awww.copdfoundation.org/Learn-More/EducationalMaterials-Resources/Educational-Video-Series.aspx

^bwww.thoracic.org/members/assemblies/assemblies/srn/questionaires/sgrq.php

^c Not an FDA-approved combination inhaled-agent treatment; approved in the European Union, under various brand names, by the European Medicines Agency.

^c Not an FDA-approved combination inhaled-agent treatment; approved in the European Union, under various brand names, by the European Medicines Agency.

CORRESPONDENCE
Michael Arnold, DO, FAAFP, Carl R. Darnall Army Medical Center, Uniformed Service University, 36065 Santa Fe Avenue, Fort Hood, TX 76544; scalpelandyardstick@gmail.com

Managing chronic obstructive pulmonary disease (COPD) presents a significant challenge to busy clinicians in many ways, especially when one is approaching the long list of inhaled pharmaceutical agents with an eye toward a cost-effective, patient-centered regimen. Inhaled agents remain expensive, with few available in generic form.

Our primary goal in this article is to detail these agents’ utility, limitations, and relative cost. Specifically, we review why the following considerations are important:

• Choose the right delivery device and drug while considering patient factors.
• Provide patient education through allied health professionals.
• Reduce environmental exposures.
• Rethink the use of inhaled corticosteroids (ICS).
• Understand the role of dual therapy and triple therapy.

Guidelines recommend reassessing inhaler technique at every visit and when evaluating treatment response.

There are numerous other treatment modalities for COPD that are recommended in national and international practice guidelines, including vaccination, pulmonary rehabilitation, home visits, phosphodiesterase-4 inhibitors, oral glucocorticoids, supplemental oxygen, and ventilatory support.¹ Discussion of those modalities is beyond the scope of this review.

Pathophysiology and pharmacotherapy targets

COPD is characterized by persistent respiratory symptoms and airflow limitation, usually due to airway or alveolar abnormalities, or both, caused by environmental and host factors.² Sustained lung parenchymal irritation results from exposure to noxious fumes generated by tobacco, pollution, chemicals, and cleaning agents. Host factors include lung immaturity at birth; genetic mutations, such as alpha-1 antitrypsin deficiency and dysregulation of elastase; and increased reactivity of bronchial smooth muscles, similar to what is seen in asthma.¹

IMAGE: © JOE GORMAN

Improving ventilation with the intention of relieving dyspnea is the goal of inhaler pharmacotherapy; targets include muscarinic receptors and beta 2-adrenergic receptors that act on bronchial smooth muscle and the autonomic nervous system. Immune modulators, such as corticosteroids, help reduce inflammation around airways.¹ Recent pharmacotherapeutic developments include combinations of inhaled medications and expanding options for devices that deliver drugs.

Delivery devices: Options and optimizing their use

Three principal types of inhaler devices are available: pressurized metered-dose inhalers (MDIs), dry-powder inhalers (DPIs), and soft-mist inhalers (SMIs). These devices, and nebulizers, facilitate medication delivery into the lungs (TABLE 1^3-9).

Errors in using inhalers affect outcome. Correct inhaler technique is essential for optimal delivery of inhaled medications. Errors in technique when using an inhaled delivery device lead to inadequate drug delivery and are associated with poor outcomes: 90% of patients make errors that are classified as critical (ie, those that reduce drug delivery) or noncritical.² Critical inhaler errors increase the risk of hospitalization and emergency department visits, and can necessitate a course of oral corticosteroids.¹⁰ Many critical errors are device specific; several such errors are described in TABLE 1.^3-9

Continue to: Patient education

Patient education is necessary to ensure that drug is delivered to the patient consistently, with the same expectation of effect seen in efficacy studies (which usually provide rigorous inhaler technique training and require demonstration of proficiency).^1,2,10 For the busy clinician, a multidisciplinary approach, discussed shortly, can help. Guidelines developed by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommend that inhaler technique be reassessed at every visit and when evaluating treatment response.¹TABLE 1^3-9 provides information on each device type, patient requirements for use, proper technique, common errors in use, and tips for optimizing delivery.

Inhaler education and assessment of technique that is provided to patients in collaboration with a clinical pharmacist, nursing staff, and a respiratory therapist can help alleviate the pressure on a time-constrained primary care physician. Furthermore, pharmacist involvement in the COPD management team meaningfully improves inhaler technique and medication adherence.^6,7 Intervention by a pharmacist correlates with a significant reduction in number of exacerbations; an increased likelihood that the patient has a COPD care plan and has received the pneumococcal vaccine; and an improvement in the mean health-related quality of life.^11,12

In primary care practices that lack robust multidisciplinary resources, we recommend utilizing virtual resources, such as educational videos, to allow face-to-face or virtual education. A free source of such resources is the COPD Foundation,^a a not-for-profit organization funded partly by industry.

Short- and long-acting inhaled medications for COPD

Each class of inhaled medication for treating COPD is discussed broadly in the following sections. TABLE 2¹ provides details about individual drugs, devices available to deliver them, and starting dosages.

Short-acting agents

These drugs are available in MDI, SMI, and nebulizer delivery devices. When portability and equipment burden are important to the patient, we recommend an MDI over a nebulizer; an MDI is as efficacious as a nebulizer in improving forced expiratory volume in 1 second (FEV₁) and reducing the length of hospital stay for exacerbations.⁴

Continue to: SABAs

Short-acting beta 2-adrenergic agonists (or beta-agonists [SABAs]). Beta-­agonists are typically used to treat exacerbations. They facilitate bronchodilation by upregulating cyclic adenosine monophosphate, preventing smooth-muscle contraction, and reducing dynamic hyperinflation. The effect of a SABA lasts 4 to 6 hours.

In general, SABAs are not recommended for daily use in stable COPD. However, they can be useful, and appropriate, for treating occasional dyspnea and can confer additional symptom improvement when used occasionally along with a long-acting beta 2-adrenergic agonist (or beta-agonist [LABA]; discussed later).¹

Continue use of a long-acting bronchodilator during exacerbations, when feasible.

Albuterol, a commonly used SABA, is less expensive than, and just as effective as, same-class levalbuterol for decreasing breathlessness associated with acute exacerbations. There is no significant difference between the 2 drugs in regard to the incidence of tachycardia or palpitations in patients with cardiovascular disease.¹³

Although no significant differences have been observed in outcomes when a nebulizer or an MDI is used to administer a SABA, it’s wise to avoid continuous SABA nebulizer therapy, due to the increased risk of disease transmission through the generation of droplets.^1,4 Instead, it’s appropriate to use an MDI regimen of 1 to 3 puffs every hour for 2 to 3 hours, followed by 1 to 3 puffs every 2 to 4 hours thereafter, based on the patient’s response.^1,4

Short-acting muscarinic antagonists (SAMAs). Muscarinic antagonists achieve bronchodilation by blocking acetylcholine on muscarinic receptors. We do not specifically recommend SAMAs over SABAs for treating COPD exacerbations in our patients: There is no difference in improvement in FEV₁ during an acute exacerbation. Nebulized delivery of a SAMA raises concern for an increase in the risk of acute narrow-angle glaucoma, a risk that can be reduced by using a mask during administration.^1,14

Continue to: SABA + SAMA

SABA + SAMA. One combination formulation of the 2 short-term classes of drugs (albuterol [SABA] + ipratropium [SAMA]), US Food and Drug Administration (FDA)–­approved for every-6-hour dosing, is available for SMI delivery devices and nebulizers. In the setting of a hospitalized patient who requires more frequent bronchodilator dosing, we use albuterol and ipratropium delivered separately (ie, dosed independently), with ipratropium dosed no more frequently than every 4 hours.

Long-acting agents

The mechanisms of long-acting agents are similar to those of their short-acting counterparts. The recommendation is to continue use of a long-acting bronchodilator during exacerbations, when feasible.¹

LABA monotherapy reduces exacerbations that result in hospitalization (number needed to treat [NNT] = 39, to prevent 1 hospitalization in an 8-month period).¹⁵ Specifically, formoterol at higher dosages reduces exacerbations requiring hospitalization (NNT = 23, to prevent 1 exacerbation in a 6-month to 3-year period).¹⁵ Evidence supports better control of symptoms when a LABA is combined with a long-acting muscarinic antagonist (LAMA; discussed shortly).^1,15

Adverse effects of LABAs include sinus tachycardia, tachyphylaxis, somatic tremors, and, less commonly, hypokalemia—the latter specific to the LABA dosage and concomitant use of a thiazide diuretic. Other adverse effects include a mild decrease in the partial pressure of O₂ and, in patients with heart failure, increased oxygen consumption. Although higher dosages are not associated with an increased incidence of nonfatal adverse events, there appears to be no additional benefit to higher dosages in regard to mortality, particularly in patients with stable COPD.^1,15

LAMA. Monotherapy with a LAMA reduces the severity of COPD symptoms and reduces the risk of exacerbations and hospitalization (NNT = 58, to prevent 1 hospitalization in a 3 to 48–month period).¹⁶ Tiotropium is superior to LABA as monotherapy in (1) reducing exacerbations (NNT = 33, to prevent 1 exacerbation in a 3 to 12–month period) and (2) being associated with a lower rate of all adverse events.¹⁷ LAMAs also confer additional benefit when used in combination with agents of other classes, which we discuss in a bit.

Continue to: The most commonly...

The most commonly reported adverse effect of a LAMA is dry mouth. Some patients report developing a bitter metallic taste in the mouth.¹

ICSs are not recommended as monotherapy in COPD.¹ However, an ICS can be combined with a LABA to reduce the risk of exacerbations in patients with severe COPD (NNT = 22, to prevent 1 exacerbation per year).¹⁸ However, this combination increases the risk of pneumonia in this population (number needed to harm [NNH] = 36, to cause 1 case of nonfatal pneumonia per year).¹⁸

ICSs increase the incidence of oropharyngeal candidiasis and hoarseness. In addition, ICSs increase the risk of pneumonia in some patients with COPD¹⁸—in particular, current smokers, patients ≥ 55 years of age, and patients with a history of pneumonia or exacerbations, a body mass index < 25, or severe COPD symptoms.^1,18 ICS therapy does reduce the risk of COPD exacerbations in patients with a history of asthma or with eosinophilia > 300 cells/μL and in those who have a history of hospitalization for COPD exacerbations.^19,20

When portability and equipment burden are important to the patient, consider a metereddose inhaler (MDI) over a nebulizer: An MDI is equally efficacious.

The risk of pneumonia is not equal across all ICS agents. Fluticasone increases the risk of pneumonia (NNH = 23, to cause 1 case of pneumonia in a 22-month period).²¹ Budesonide showed no statistically significant increase in risk of pneumonia.²² However, further studies on the risk of pneumonia with budesonide are needed because those cited in the Cochrane review²¹ were much smaller trials, compared to trials of fluticasone, and of low-to-moderate quality. Furthermore, evidence is mixed whether ICS monotherapy in COPD worsens mortality during an 18-month study period.^21-23

For these reasons, it’s reasonable to (1) exercise caution when considering the addition of an ICS to LABA therapy and (2) limit such a combination to the setting of severe disease (as discussed already).

Continue to: LABA + LAMA

LABA + LAMA. In a trial of patients with moderate-to-severe COPD, combining a LABA and a LAMA did not reduce the risk of exacerbations or hospitalizations, compared to LABA or LAMA monotherapy, but did improve subjects’ reported daily symptoms and quality of life scores (using the St. George’s Respiratory Questionnaire^b; NNT = 14 [LAMA monotherapy] and NNT = 9 [LABA monotherapy], both in a 3 to 12–month period).²⁴ However, another study that looked at patients with moderate-to-severe COPD found that combining a LABA and a LAMA led to fewer exacerbations (NNT = 22, to prevent 1 exacerbation in a 3 to 12–month period) and a lower risk of pneumonia (NNT = 93, to prevent 1 case of pneumonia in a 3 to 12–month period) than LABA + ICS.²⁵

LABA + ICS. This dual therapy is falling out of favor, compared to treatment with LABA + LAMA, because LABA + ICS formulations are less effective at reducing exacerbations and increase the risk of pneumonia in patients with moderate-to-severe COPD.^1,25 However, LABA + ICS therapy still has a role in a subset of patients with COPD (discussed in the section on ICS). A LABA combined with an ICS does reduce exacerbations in patients with severe COPD (NNT = 22, to prevent 1 exacerbation per year).¹⁸ Expect that the reported rates of candidiasis, hoarseness, and pneumonia associated with an ICS will be similar with LABA + ICS.¹⁸

LABA + LAMA + ICS. These are the newest combination inhaled agents approved for clinical use. It is recommended that escalation to such triple therapy be reserved for patients with persistent dyspnea on LAMA + LABA therapy and who have the factors (previously described) that suggest benefit from adding an ICS.¹ Several clinical trials have provided guidance:

• In the 2018 TRIBUTE trial,²⁶ beclometasone (ICS) + formoterol (LABA) + glycopyrronium (LAMA) ^c outperformed indacaterol (LABA) + glycopyrronium for preventing moderate-to-severe exacerbations (NNT = 11, to prevent 1 exacerbation per year) in patients with symptomatic COPD who have severe or very severe airflow resistance and a history of a moderate-to-severe exacerbation during the previous year.
• In the 2017 TRINITY trial,²⁷ beclometasone + formoterol + glycopyrronium^c outperformed tiotropium (LAMA) in preventing moderate-to-severe exacerbations (NNT = 9, to prevent 1 exacerbation per year) in patients with an FEV₁ < 50% and a history of ≥ 1 moderate-to-severe exacerbation during the previous year.
• In the 2020 ETHOS trial,²⁸ budesonide + formoterol + glycopyrronium (approved by the FDA in 2020 under the brand name Breztri) outperformed both glycopyrrolate + formoterol (LABA) and budesonide (ICS) + formoterol in preventing moderate-to-severe exacerbations (NNT = 56 and 34, respectively, to prevent 1 exacerbation per year) in patients with moderate-to-severe COPD who had a history of ≥ 1 exacerbation in the previous year. Additionally, higher-dose budesonide + formoterol + glycopyrronium reduced 1-year mortality to a modest degree compared to glycopyrrolate + formoterol (NNT = 100, to prevent 1 death in a 12-month period).
• A 2016 Cochrane review that compared tiotropium + LABA + ICS to tiotropium monotherapy²⁹ showed improvement in FEV₁ and patient-reported symptoms and quality of life scores. However, the review showed no difference in exacerbations or hospitalizations over a 1-year period.

Mitigating environmental exposures that affect inhaler medication efficacy

Tobacco smoke. Emphasizing smoking cessation is highly relevant in patients who are still smoking. Smoking impedes the efficacy of ICSs in reducing exacerbations of COPD.³⁰ Along with improved lung function, former smokers with COPD experience fewer exacerbations (NNT = 73, to prevent 1 exacerbation in a 4-year period for all former smokers; NNT = 33, to do so for smokers who quit > 10 years ago).^31,32

The continuous use of shortacting betaagonist nebulizer therapy can increase the risk of disease transmission through the generation of droplets.

A 2005 Veterans Health Administration study showed reduced mortality in smokers who were enrolled in a 10-week smoking cessation program, had access to nicotine replacement therapy, and received strong physician messaging.³³ Despite a 20% to 25% quit rate, the NNT was 56 to prevent 1 death in 14.5 years across the entire group. It is worth having patients take advantage of this 3-pronged approach if it is available in your community or health system.

Continue to: Exposure to air pollution

Exposure to air pollution. Air pollutants other than tobacco smoke remain important modifiable factors that impact COPD. These include organic and inorganic dusts, chemical agents and fumes, and burning of solid biomass (eg, wood, coal) indoors in open fires or poorly functioning stoves.¹ With this risk in mind, counsel patients regarding efficient home ventilation, use of nonpolluting cooking stoves, and the reduction of occupational exposure to these potential irritants.

GOLD approach to starting and adjusting inhaled therapy

Initiating inhaled therapy

A good resource for family physicians is the GOLD refined ABCD assessment scheme for initiating inhaler therapy that integrates symptoms and exacerbations (TABLE 3¹). To assess the severity of dyspnea, either the Modified Medical Research Council (mMRC) Questionnaire or COPD Assessment Test (CAT) can be used. A moderate exacerbation requires an oral corticosteroid or antibiotic, or both; a severe exacerbation requires an emergency department visit or hospitalization, or both. TABLE 3¹ offers a guide to choosing initial therapy based on these factors.¹

Following up on and adjusting an inhaler regimen

Adjust inhaler pharmacotherapy based on whether exacerbations or daily symptoms of dyspnea are more bothersome to the patient. Escalation of therapy involves adding other long-acting agents and is warranted for patients with exacerbations or severe or worsening dyspnea. Before escalating therapy with additional agents, reassess the appropriateness of the delivery device that the patient has been using and assess their adherence to the prescribed regimen.¹

Dyspnea predominates. Escalate with LABA + LAMA. For a patient already taking an ICS, consider removing that ICS if the original indication was inappropriate, no response to treatment has been noted, or pneumonia develops.¹

Exacerbations predominate. Escalate with LABA + LAMA or with LABA + ICS. Consider adding an ICS in patients who have a history of asthma, eosinophilia > 300 cells/uL, or eosinophilia > 100 cells/uL and 2 moderate exacerbations or 1 severe (ie, hospitalizing) exacerbation. This addition of an ICS results in dual or triple therapy (ie, either LABA + ICS or LABA + LAMA + ICS).¹

Continue to: Unclear what predominates?

Unclear what predominates? Follow the exacerbation predominance pathway.¹

Additional decision-making might be necessary in several circumstances:

• For the patient who requires further titration beyond these pathways, consider triple therapy as LABA + LAMA + ICS, unless the eosinophil count is < 100 cell/μL.¹
• Consider de-escalating ICS therapy if the patient develops pneumonia, there is a lack of demonstrated benefit, or the initial indication was uncertain or inappropriate.
• For the patient who continues to have significant dyspnea despite dual or triple therapy, consider investigating and treating other causes of dyspnea.¹

Last, keep in mind that evidence is limited regarding escalating the dosage of these agents (1) beyond what is listed in TABLE 2¹ and (2) in specific instances mentioned in the discussion of each inhaler class.

^awww.copdfoundation.org/Learn-More/EducationalMaterials-Resources/Educational-Video-Series.aspx

^bwww.thoracic.org/members/assemblies/assemblies/srn/questionaires/sgrq.php

^c Not an FDA-approved combination inhaled-agent treatment; approved in the European Union, under various brand names, by the European Medicines Agency.

^c Not an FDA-approved combination inhaled-agent treatment; approved in the European Union, under various brand names, by the European Medicines Agency.

CORRESPONDENCE
Michael Arnold, DO, FAAFP, Carl R. Darnall Army Medical Center, Uniformed Service University, 36065 Santa Fe Avenue, Fort Hood, TX 76544; scalpelandyardstick@gmail.com

Managing chronic obstructive pulmonary disease (COPD) presents a significant challenge to busy clinicians in many ways, especially when one is approaching the long list of inhaled pharmaceutical agents with an eye toward a cost-effective, patient-centered regimen. Inhaled agents remain expensive, with few available in generic form.

Our primary goal in this article is to detail these agents’ utility, limitations, and relative cost. Specifically, we review why the following considerations are important:

• Choose the right delivery device and drug while considering patient factors.
• Provide patient education through allied health professionals.
• Reduce environmental exposures.
• Rethink the use of inhaled corticosteroids (ICS).
• Understand the role of dual therapy and triple therapy.

Guidelines recommend reassessing inhaler technique at every visit and when evaluating treatment response.

There are numerous other treatment modalities for COPD that are recommended in national and international practice guidelines, including vaccination, pulmonary rehabilitation, home visits, phosphodiesterase-4 inhibitors, oral glucocorticoids, supplemental oxygen, and ventilatory support.¹ Discussion of those modalities is beyond the scope of this review.

Pathophysiology and pharmacotherapy targets

COPD is characterized by persistent respiratory symptoms and airflow limitation, usually due to airway or alveolar abnormalities, or both, caused by environmental and host factors.² Sustained lung parenchymal irritation results from exposure to noxious fumes generated by tobacco, pollution, chemicals, and cleaning agents. Host factors include lung immaturity at birth; genetic mutations, such as alpha-1 antitrypsin deficiency and dysregulation of elastase; and increased reactivity of bronchial smooth muscles, similar to what is seen in asthma.¹

IMAGE: © JOE GORMAN

Improving ventilation with the intention of relieving dyspnea is the goal of inhaler pharmacotherapy; targets include muscarinic receptors and beta 2-adrenergic receptors that act on bronchial smooth muscle and the autonomic nervous system. Immune modulators, such as corticosteroids, help reduce inflammation around airways.¹ Recent pharmacotherapeutic developments include combinations of inhaled medications and expanding options for devices that deliver drugs.

Delivery devices: Options and optimizing their use

Three principal types of inhaler devices are available: pressurized metered-dose inhalers (MDIs), dry-powder inhalers (DPIs), and soft-mist inhalers (SMIs). These devices, and nebulizers, facilitate medication delivery into the lungs (TABLE 1^3-9).

Errors in using inhalers affect outcome. Correct inhaler technique is essential for optimal delivery of inhaled medications. Errors in technique when using an inhaled delivery device lead to inadequate drug delivery and are associated with poor outcomes: 90% of patients make errors that are classified as critical (ie, those that reduce drug delivery) or noncritical.² Critical inhaler errors increase the risk of hospitalization and emergency department visits, and can necessitate a course of oral corticosteroids.¹⁰ Many critical errors are device specific; several such errors are described in TABLE 1.^3-9

Continue to: Patient education

Patient education is necessary to ensure that drug is delivered to the patient consistently, with the same expectation of effect seen in efficacy studies (which usually provide rigorous inhaler technique training and require demonstration of proficiency).^1,2,10 For the busy clinician, a multidisciplinary approach, discussed shortly, can help. Guidelines developed by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommend that inhaler technique be reassessed at every visit and when evaluating treatment response.¹TABLE 1^3-9 provides information on each device type, patient requirements for use, proper technique, common errors in use, and tips for optimizing delivery.

Inhaler education and assessment of technique that is provided to patients in collaboration with a clinical pharmacist, nursing staff, and a respiratory therapist can help alleviate the pressure on a time-constrained primary care physician. Furthermore, pharmacist involvement in the COPD management team meaningfully improves inhaler technique and medication adherence.^6,7 Intervention by a pharmacist correlates with a significant reduction in number of exacerbations; an increased likelihood that the patient has a COPD care plan and has received the pneumococcal vaccine; and an improvement in the mean health-related quality of life.^11,12

In primary care practices that lack robust multidisciplinary resources, we recommend utilizing virtual resources, such as educational videos, to allow face-to-face or virtual education. A free source of such resources is the COPD Foundation,^a a not-for-profit organization funded partly by industry.

Short- and long-acting inhaled medications for COPD

Each class of inhaled medication for treating COPD is discussed broadly in the following sections. TABLE 2¹ provides details about individual drugs, devices available to deliver them, and starting dosages.

Short-acting agents

These drugs are available in MDI, SMI, and nebulizer delivery devices. When portability and equipment burden are important to the patient, we recommend an MDI over a nebulizer; an MDI is as efficacious as a nebulizer in improving forced expiratory volume in 1 second (FEV₁) and reducing the length of hospital stay for exacerbations.⁴

Continue to: SABAs

Short-acting beta 2-adrenergic agonists (or beta-agonists [SABAs]). Beta-­agonists are typically used to treat exacerbations. They facilitate bronchodilation by upregulating cyclic adenosine monophosphate, preventing smooth-muscle contraction, and reducing dynamic hyperinflation. The effect of a SABA lasts 4 to 6 hours.

In general, SABAs are not recommended for daily use in stable COPD. However, they can be useful, and appropriate, for treating occasional dyspnea and can confer additional symptom improvement when used occasionally along with a long-acting beta 2-adrenergic agonist (or beta-agonist [LABA]; discussed later).¹

Continue use of a long-acting bronchodilator during exacerbations, when feasible.

Albuterol, a commonly used SABA, is less expensive than, and just as effective as, same-class levalbuterol for decreasing breathlessness associated with acute exacerbations. There is no significant difference between the 2 drugs in regard to the incidence of tachycardia or palpitations in patients with cardiovascular disease.¹³

Although no significant differences have been observed in outcomes when a nebulizer or an MDI is used to administer a SABA, it’s wise to avoid continuous SABA nebulizer therapy, due to the increased risk of disease transmission through the generation of droplets.^1,4 Instead, it’s appropriate to use an MDI regimen of 1 to 3 puffs every hour for 2 to 3 hours, followed by 1 to 3 puffs every 2 to 4 hours thereafter, based on the patient’s response.^1,4

Short-acting muscarinic antagonists (SAMAs). Muscarinic antagonists achieve bronchodilation by blocking acetylcholine on muscarinic receptors. We do not specifically recommend SAMAs over SABAs for treating COPD exacerbations in our patients: There is no difference in improvement in FEV₁ during an acute exacerbation. Nebulized delivery of a SAMA raises concern for an increase in the risk of acute narrow-angle glaucoma, a risk that can be reduced by using a mask during administration.^1,14

Continue to: SABA + SAMA

SABA + SAMA. One combination formulation of the 2 short-term classes of drugs (albuterol [SABA] + ipratropium [SAMA]), US Food and Drug Administration (FDA)–­approved for every-6-hour dosing, is available for SMI delivery devices and nebulizers. In the setting of a hospitalized patient who requires more frequent bronchodilator dosing, we use albuterol and ipratropium delivered separately (ie, dosed independently), with ipratropium dosed no more frequently than every 4 hours.

Long-acting agents

The mechanisms of long-acting agents are similar to those of their short-acting counterparts. The recommendation is to continue use of a long-acting bronchodilator during exacerbations, when feasible.¹

LABA monotherapy reduces exacerbations that result in hospitalization (number needed to treat [NNT] = 39, to prevent 1 hospitalization in an 8-month period).¹⁵ Specifically, formoterol at higher dosages reduces exacerbations requiring hospitalization (NNT = 23, to prevent 1 exacerbation in a 6-month to 3-year period).¹⁵ Evidence supports better control of symptoms when a LABA is combined with a long-acting muscarinic antagonist (LAMA; discussed shortly).^1,15

Adverse effects of LABAs include sinus tachycardia, tachyphylaxis, somatic tremors, and, less commonly, hypokalemia—the latter specific to the LABA dosage and concomitant use of a thiazide diuretic. Other adverse effects include a mild decrease in the partial pressure of O₂ and, in patients with heart failure, increased oxygen consumption. Although higher dosages are not associated with an increased incidence of nonfatal adverse events, there appears to be no additional benefit to higher dosages in regard to mortality, particularly in patients with stable COPD.^1,15

LAMA. Monotherapy with a LAMA reduces the severity of COPD symptoms and reduces the risk of exacerbations and hospitalization (NNT = 58, to prevent 1 hospitalization in a 3 to 48–month period).¹⁶ Tiotropium is superior to LABA as monotherapy in (1) reducing exacerbations (NNT = 33, to prevent 1 exacerbation in a 3 to 12–month period) and (2) being associated with a lower rate of all adverse events.¹⁷ LAMAs also confer additional benefit when used in combination with agents of other classes, which we discuss in a bit.

Continue to: The most commonly...

The most commonly reported adverse effect of a LAMA is dry mouth. Some patients report developing a bitter metallic taste in the mouth.¹

ICSs are not recommended as monotherapy in COPD.¹ However, an ICS can be combined with a LABA to reduce the risk of exacerbations in patients with severe COPD (NNT = 22, to prevent 1 exacerbation per year).¹⁸ However, this combination increases the risk of pneumonia in this population (number needed to harm [NNH] = 36, to cause 1 case of nonfatal pneumonia per year).¹⁸

ICSs increase the incidence of oropharyngeal candidiasis and hoarseness. In addition, ICSs increase the risk of pneumonia in some patients with COPD¹⁸—in particular, current smokers, patients ≥ 55 years of age, and patients with a history of pneumonia or exacerbations, a body mass index < 25, or severe COPD symptoms.^1,18 ICS therapy does reduce the risk of COPD exacerbations in patients with a history of asthma or with eosinophilia > 300 cells/μL and in those who have a history of hospitalization for COPD exacerbations.^19,20

When portability and equipment burden are important to the patient, consider a metereddose inhaler (MDI) over a nebulizer: An MDI is equally efficacious.

The risk of pneumonia is not equal across all ICS agents. Fluticasone increases the risk of pneumonia (NNH = 23, to cause 1 case of pneumonia in a 22-month period).²¹ Budesonide showed no statistically significant increase in risk of pneumonia.²² However, further studies on the risk of pneumonia with budesonide are needed because those cited in the Cochrane review²¹ were much smaller trials, compared to trials of fluticasone, and of low-to-moderate quality. Furthermore, evidence is mixed whether ICS monotherapy in COPD worsens mortality during an 18-month study period.^21-23

For these reasons, it’s reasonable to (1) exercise caution when considering the addition of an ICS to LABA therapy and (2) limit such a combination to the setting of severe disease (as discussed already).

Continue to: LABA + LAMA

LABA + LAMA. In a trial of patients with moderate-to-severe COPD, combining a LABA and a LAMA did not reduce the risk of exacerbations or hospitalizations, compared to LABA or LAMA monotherapy, but did improve subjects’ reported daily symptoms and quality of life scores (using the St. George’s Respiratory Questionnaire^b; NNT = 14 [LAMA monotherapy] and NNT = 9 [LABA monotherapy], both in a 3 to 12–month period).²⁴ However, another study that looked at patients with moderate-to-severe COPD found that combining a LABA and a LAMA led to fewer exacerbations (NNT = 22, to prevent 1 exacerbation in a 3 to 12–month period) and a lower risk of pneumonia (NNT = 93, to prevent 1 case of pneumonia in a 3 to 12–month period) than LABA + ICS.²⁵

LABA + ICS. This dual therapy is falling out of favor, compared to treatment with LABA + LAMA, because LABA + ICS formulations are less effective at reducing exacerbations and increase the risk of pneumonia in patients with moderate-to-severe COPD.^1,25 However, LABA + ICS therapy still has a role in a subset of patients with COPD (discussed in the section on ICS). A LABA combined with an ICS does reduce exacerbations in patients with severe COPD (NNT = 22, to prevent 1 exacerbation per year).¹⁸ Expect that the reported rates of candidiasis, hoarseness, and pneumonia associated with an ICS will be similar with LABA + ICS.¹⁸

LABA + LAMA + ICS. These are the newest combination inhaled agents approved for clinical use. It is recommended that escalation to such triple therapy be reserved for patients with persistent dyspnea on LAMA + LABA therapy and who have the factors (previously described) that suggest benefit from adding an ICS.¹ Several clinical trials have provided guidance:

• In the 2018 TRIBUTE trial,²⁶ beclometasone (ICS) + formoterol (LABA) + glycopyrronium (LAMA) ^c outperformed indacaterol (LABA) + glycopyrronium for preventing moderate-to-severe exacerbations (NNT = 11, to prevent 1 exacerbation per year) in patients with symptomatic COPD who have severe or very severe airflow resistance and a history of a moderate-to-severe exacerbation during the previous year.
• In the 2017 TRINITY trial,²⁷ beclometasone + formoterol + glycopyrronium^c outperformed tiotropium (LAMA) in preventing moderate-to-severe exacerbations (NNT = 9, to prevent 1 exacerbation per year) in patients with an FEV₁ < 50% and a history of ≥ 1 moderate-to-severe exacerbation during the previous year.
• In the 2020 ETHOS trial,²⁸ budesonide + formoterol + glycopyrronium (approved by the FDA in 2020 under the brand name Breztri) outperformed both glycopyrrolate + formoterol (LABA) and budesonide (ICS) + formoterol in preventing moderate-to-severe exacerbations (NNT = 56 and 34, respectively, to prevent 1 exacerbation per year) in patients with moderate-to-severe COPD who had a history of ≥ 1 exacerbation in the previous year. Additionally, higher-dose budesonide + formoterol + glycopyrronium reduced 1-year mortality to a modest degree compared to glycopyrrolate + formoterol (NNT = 100, to prevent 1 death in a 12-month period).
• A 2016 Cochrane review that compared tiotropium + LABA + ICS to tiotropium monotherapy²⁹ showed improvement in FEV₁ and patient-reported symptoms and quality of life scores. However, the review showed no difference in exacerbations or hospitalizations over a 1-year period.

Mitigating environmental exposures that affect inhaler medication efficacy

Tobacco smoke. Emphasizing smoking cessation is highly relevant in patients who are still smoking. Smoking impedes the efficacy of ICSs in reducing exacerbations of COPD.³⁰ Along with improved lung function, former smokers with COPD experience fewer exacerbations (NNT = 73, to prevent 1 exacerbation in a 4-year period for all former smokers; NNT = 33, to do so for smokers who quit > 10 years ago).^31,32

The continuous use of shortacting betaagonist nebulizer therapy can increase the risk of disease transmission through the generation of droplets.

A 2005 Veterans Health Administration study showed reduced mortality in smokers who were enrolled in a 10-week smoking cessation program, had access to nicotine replacement therapy, and received strong physician messaging.³³ Despite a 20% to 25% quit rate, the NNT was 56 to prevent 1 death in 14.5 years across the entire group. It is worth having patients take advantage of this 3-pronged approach if it is available in your community or health system.

Continue to: Exposure to air pollution

Exposure to air pollution. Air pollutants other than tobacco smoke remain important modifiable factors that impact COPD. These include organic and inorganic dusts, chemical agents and fumes, and burning of solid biomass (eg, wood, coal) indoors in open fires or poorly functioning stoves.¹ With this risk in mind, counsel patients regarding efficient home ventilation, use of nonpolluting cooking stoves, and the reduction of occupational exposure to these potential irritants.

GOLD approach to starting and adjusting inhaled therapy

Initiating inhaled therapy

A good resource for family physicians is the GOLD refined ABCD assessment scheme for initiating inhaler therapy that integrates symptoms and exacerbations (TABLE 3¹). To assess the severity of dyspnea, either the Modified Medical Research Council (mMRC) Questionnaire or COPD Assessment Test (CAT) can be used. A moderate exacerbation requires an oral corticosteroid or antibiotic, or both; a severe exacerbation requires an emergency department visit or hospitalization, or both. TABLE 3¹ offers a guide to choosing initial therapy based on these factors.¹

Following up on and adjusting an inhaler regimen

Adjust inhaler pharmacotherapy based on whether exacerbations or daily symptoms of dyspnea are more bothersome to the patient. Escalation of therapy involves adding other long-acting agents and is warranted for patients with exacerbations or severe or worsening dyspnea. Before escalating therapy with additional agents, reassess the appropriateness of the delivery device that the patient has been using and assess their adherence to the prescribed regimen.¹

Dyspnea predominates. Escalate with LABA + LAMA. For a patient already taking an ICS, consider removing that ICS if the original indication was inappropriate, no response to treatment has been noted, or pneumonia develops.¹

Exacerbations predominate. Escalate with LABA + LAMA or with LABA + ICS. Consider adding an ICS in patients who have a history of asthma, eosinophilia > 300 cells/uL, or eosinophilia > 100 cells/uL and 2 moderate exacerbations or 1 severe (ie, hospitalizing) exacerbation. This addition of an ICS results in dual or triple therapy (ie, either LABA + ICS or LABA + LAMA + ICS).¹

Continue to: Unclear what predominates?

Unclear what predominates? Follow the exacerbation predominance pathway.¹

Additional decision-making might be necessary in several circumstances:

• For the patient who requires further titration beyond these pathways, consider triple therapy as LABA + LAMA + ICS, unless the eosinophil count is < 100 cell/μL.¹
• Consider de-escalating ICS therapy if the patient develops pneumonia, there is a lack of demonstrated benefit, or the initial indication was uncertain or inappropriate.
• For the patient who continues to have significant dyspnea despite dual or triple therapy, consider investigating and treating other causes of dyspnea.¹

Last, keep in mind that evidence is limited regarding escalating the dosage of these agents (1) beyond what is listed in TABLE 2¹ and (2) in specific instances mentioned in the discussion of each inhaler class.

^awww.copdfoundation.org/Learn-More/EducationalMaterials-Resources/Educational-Video-Series.aspx

^bwww.thoracic.org/members/assemblies/assemblies/srn/questionaires/sgrq.php

^c Not an FDA-approved combination inhaled-agent treatment; approved in the European Union, under various brand names, by the European Medicines Agency.

^c Not an FDA-approved combination inhaled-agent treatment; approved in the European Union, under various brand names, by the European Medicines Agency.

CORRESPONDENCE
Michael Arnold, DO, FAAFP, Carl R. Darnall Army Medical Center, Uniformed Service University, 36065 Santa Fe Avenue, Fort Hood, TX 76544; scalpelandyardstick@gmail.com

A 58-year-old man presents to your office with a 2-day history of moderate (6/10) left lower quadrant pain, mild fever (none currently), 2 episodes of vomiting, no diarrhea, and no relief with OTC medications. You suspect diverticulitis and obtain an abdominal CT scan, which shows mild, uncomplicated (Hinchey stage 1a) diverticulitis. How would you treat this patient?

Diverticulitis is common; each year, about 200,000 people in the United States are admitted to the hospital because of it.^2,3 Health care providers typically treat diverticular disease with antibiotics and bowel rest.^2,3 While severe forms of diverticulitis often require parenteral antibiotics and/or surgery, practitioners are increasingly managing the condition with oral antibiotics.⁴

One previous randomized controlled trial (RCT; N = 623) found that antibiotic treatment for acute uncomplicated diverticulitis did not speed recovery or prevent complications (perforation or abscess formation) or recurrence at 12 months.⁵ The study’s strengths included limiting enrollment to people with CT-proven diverticulitis, using a good randomization and concealment process, and employing intention-to-treat analysis. The study was limited by the lack of a standardized antibiotic regimen across centers, previous diverticulitis diagnoses in 40% of patients, nonuniform follow-up processes to confirm anatomic resolution, and the lack of assessment to confirm resolution.⁵

STUDY SUMMARY

Watchful waiting just as effective as antibiotics

This newer study was a single-blind RCT that compared treatment with antibiotics to observation among 528 adults in the Netherlands. Patients were enrolled if they had CT-proven, primary, left-sided, uncomplicated acute diverticulitis (Hinchey stage 1a and 1b).¹ (The Hinchey classification is based on radiologic findings, with 0 for clinical diverticulitis only, 1a for confined pericolic inflammation or phlegmon, and 1b for pericolic or mesocolic abscess.⁶) Exclusion criteria included suspicion of colonic cancer by CT or ultrasound (US), previous CT/US-proven diverticulitis, sepsis, pregnancy, or antibiotic use in the previous 4 weeks.¹

Observational vs antibiotic treatment. Enrolled patients were randomly assigned to receive amoxicillin-clavulanate (1,200 mg by IV qid for at least 48 hours, followed by 625 mg po tid, for 10 total days; n = 266) or to be observed (n = 262). Randomization was performed by computer, with a random varying block size and stratification by Hinchey classification and center; allocation was concealed. The investigators were masked to the allocation until all analyses were completed.¹

The primary outcome was the time to functional recovery (resumption of pre-illness work activities) during a 6-month follow-up period. Secondary outcomes included hospital readmission rate; complicated, ongoing, and recurrent diverticulitis; sigmoid resection; other nonsurgical intervention; antibiotic adverse effects; and all-cause mortality.

Results. Median recovery time for observational treatment was not inferior to antibiotic treatment (14 d vs 12 d; hazard ratio for functional recovery, 0.91). Observation was not inferior to antibiotics for any of the secondary endpoints at 6 and 12 months of follow-up: complicated diverticulitis (3.8% vs 2.6%, respectively), recurrent diverticulitis (3.4% vs 3%), readmission (17.6% vs 12%), or adverse events (48.5% vs 54.5%). Initial hospitalization length of stay was shorter in the observation group (2 vs 3 d). The researchers conducted a 24-month telephone follow-up, but no differences from the 12-month follow-up were noted.¹

Continue to: WHAT'S NEW

WHAT’S NEW

Study looked at true patient-oriented ­outcome

Previous studies of treatment options for acute uncomplicated diverticulitis looked at short-term outcomes, or at readmission, recurrence, and surgical intervention rate or requirement for percutaneous drainage.^7,8 This study is the first to look at functional return to work (a true patient-oriented outcome). And it is the only study to follow up at 24 months to gauge long-term outcomes with observational treatment.

CAVEATS

Can’t generalize to worse cases

It is worth noting that the findings of this study apply only to the mildest form of CT-proven acute diverticulitis (those patients classified as having Hinchey 1a disease) and are not generalizable to patients with more severe forms. Not enough patients with Hinchey 1b acute diverticulitis were enrolled in the study to reach any conclusions about treatment.

Various guidelines issued outside the United States recommend antibiotics for uncomplicated diverticulitis; however, the American Gastroenterological Association (AGA) indicates that antibiotics should be used selectively.^1,9,10 This recommendation was based on an emerging understanding that diverticulitis may be more inflammatory than infectious in nature. The AGA guideline authors acknowledge that their conclusion was based on low-quality evidence.⁹

CHALLENGES TO IMPLEMENTATION

None to speak of

We see no challenges to implementing this recommendation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2018. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2018;67[7]:435-436,438).

A 58-year-old man presents to your office with a 2-day history of moderate (6/10) left lower quadrant pain, mild fever (none currently), 2 episodes of vomiting, no diarrhea, and no relief with OTC medications. You suspect diverticulitis and obtain an abdominal CT scan, which shows mild, uncomplicated (Hinchey stage 1a) diverticulitis. How would you treat this patient?

Diverticulitis is common; each year, about 200,000 people in the United States are admitted to the hospital because of it.^2,3 Health care providers typically treat diverticular disease with antibiotics and bowel rest.^2,3 While severe forms of diverticulitis often require parenteral antibiotics and/or surgery, practitioners are increasingly managing the condition with oral antibiotics.⁴

One previous randomized controlled trial (RCT; N = 623) found that antibiotic treatment for acute uncomplicated diverticulitis did not speed recovery or prevent complications (perforation or abscess formation) or recurrence at 12 months.⁵ The study’s strengths included limiting enrollment to people with CT-proven diverticulitis, using a good randomization and concealment process, and employing intention-to-treat analysis. The study was limited by the lack of a standardized antibiotic regimen across centers, previous diverticulitis diagnoses in 40% of patients, nonuniform follow-up processes to confirm anatomic resolution, and the lack of assessment to confirm resolution.⁵

STUDY SUMMARY

Watchful waiting just as effective as antibiotics

This newer study was a single-blind RCT that compared treatment with antibiotics to observation among 528 adults in the Netherlands. Patients were enrolled if they had CT-proven, primary, left-sided, uncomplicated acute diverticulitis (Hinchey stage 1a and 1b).¹ (The Hinchey classification is based on radiologic findings, with 0 for clinical diverticulitis only, 1a for confined pericolic inflammation or phlegmon, and 1b for pericolic or mesocolic abscess.⁶) Exclusion criteria included suspicion of colonic cancer by CT or ultrasound (US), previous CT/US-proven diverticulitis, sepsis, pregnancy, or antibiotic use in the previous 4 weeks.¹

Observational vs antibiotic treatment. Enrolled patients were randomly assigned to receive amoxicillin-clavulanate (1,200 mg by IV qid for at least 48 hours, followed by 625 mg po tid, for 10 total days; n = 266) or to be observed (n = 262). Randomization was performed by computer, with a random varying block size and stratification by Hinchey classification and center; allocation was concealed. The investigators were masked to the allocation until all analyses were completed.¹

The primary outcome was the time to functional recovery (resumption of pre-illness work activities) during a 6-month follow-up period. Secondary outcomes included hospital readmission rate; complicated, ongoing, and recurrent diverticulitis; sigmoid resection; other nonsurgical intervention; antibiotic adverse effects; and all-cause mortality.

Results. Median recovery time for observational treatment was not inferior to antibiotic treatment (14 d vs 12 d; hazard ratio for functional recovery, 0.91). Observation was not inferior to antibiotics for any of the secondary endpoints at 6 and 12 months of follow-up: complicated diverticulitis (3.8% vs 2.6%, respectively), recurrent diverticulitis (3.4% vs 3%), readmission (17.6% vs 12%), or adverse events (48.5% vs 54.5%). Initial hospitalization length of stay was shorter in the observation group (2 vs 3 d). The researchers conducted a 24-month telephone follow-up, but no differences from the 12-month follow-up were noted.¹

Continue to: WHAT'S NEW

WHAT’S NEW

Study looked at true patient-oriented ­outcome

Previous studies of treatment options for acute uncomplicated diverticulitis looked at short-term outcomes, or at readmission, recurrence, and surgical intervention rate or requirement for percutaneous drainage.^7,8 This study is the first to look at functional return to work (a true patient-oriented outcome). And it is the only study to follow up at 24 months to gauge long-term outcomes with observational treatment.

CAVEATS

Can’t generalize to worse cases

It is worth noting that the findings of this study apply only to the mildest form of CT-proven acute diverticulitis (those patients classified as having Hinchey 1a disease) and are not generalizable to patients with more severe forms. Not enough patients with Hinchey 1b acute diverticulitis were enrolled in the study to reach any conclusions about treatment.

Various guidelines issued outside the United States recommend antibiotics for uncomplicated diverticulitis; however, the American Gastroenterological Association (AGA) indicates that antibiotics should be used selectively.^1,9,10 This recommendation was based on an emerging understanding that diverticulitis may be more inflammatory than infectious in nature. The AGA guideline authors acknowledge that their conclusion was based on low-quality evidence.⁹

CHALLENGES TO IMPLEMENTATION

None to speak of

We see no challenges to implementing this recommendation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2018. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2018;67[7]:435-436,438).

A 58-year-old man presents to your office with a 2-day history of moderate (6/10) left lower quadrant pain, mild fever (none currently), 2 episodes of vomiting, no diarrhea, and no relief with OTC medications. You suspect diverticulitis and obtain an abdominal CT scan, which shows mild, uncomplicated (Hinchey stage 1a) diverticulitis. How would you treat this patient?

Diverticulitis is common; each year, about 200,000 people in the United States are admitted to the hospital because of it.^2,3 Health care providers typically treat diverticular disease with antibiotics and bowel rest.^2,3 While severe forms of diverticulitis often require parenteral antibiotics and/or surgery, practitioners are increasingly managing the condition with oral antibiotics.⁴

One previous randomized controlled trial (RCT; N = 623) found that antibiotic treatment for acute uncomplicated diverticulitis did not speed recovery or prevent complications (perforation or abscess formation) or recurrence at 12 months.⁵ The study’s strengths included limiting enrollment to people with CT-proven diverticulitis, using a good randomization and concealment process, and employing intention-to-treat analysis. The study was limited by the lack of a standardized antibiotic regimen across centers, previous diverticulitis diagnoses in 40% of patients, nonuniform follow-up processes to confirm anatomic resolution, and the lack of assessment to confirm resolution.⁵

STUDY SUMMARY

Watchful waiting just as effective as antibiotics

This newer study was a single-blind RCT that compared treatment with antibiotics to observation among 528 adults in the Netherlands. Patients were enrolled if they had CT-proven, primary, left-sided, uncomplicated acute diverticulitis (Hinchey stage 1a and 1b).¹ (The Hinchey classification is based on radiologic findings, with 0 for clinical diverticulitis only, 1a for confined pericolic inflammation or phlegmon, and 1b for pericolic or mesocolic abscess.⁶) Exclusion criteria included suspicion of colonic cancer by CT or ultrasound (US), previous CT/US-proven diverticulitis, sepsis, pregnancy, or antibiotic use in the previous 4 weeks.¹

Observational vs antibiotic treatment. Enrolled patients were randomly assigned to receive amoxicillin-clavulanate (1,200 mg by IV qid for at least 48 hours, followed by 625 mg po tid, for 10 total days; n = 266) or to be observed (n = 262). Randomization was performed by computer, with a random varying block size and stratification by Hinchey classification and center; allocation was concealed. The investigators were masked to the allocation until all analyses were completed.¹

The primary outcome was the time to functional recovery (resumption of pre-illness work activities) during a 6-month follow-up period. Secondary outcomes included hospital readmission rate; complicated, ongoing, and recurrent diverticulitis; sigmoid resection; other nonsurgical intervention; antibiotic adverse effects; and all-cause mortality.

Results. Median recovery time for observational treatment was not inferior to antibiotic treatment (14 d vs 12 d; hazard ratio for functional recovery, 0.91). Observation was not inferior to antibiotics for any of the secondary endpoints at 6 and 12 months of follow-up: complicated diverticulitis (3.8% vs 2.6%, respectively), recurrent diverticulitis (3.4% vs 3%), readmission (17.6% vs 12%), or adverse events (48.5% vs 54.5%). Initial hospitalization length of stay was shorter in the observation group (2 vs 3 d). The researchers conducted a 24-month telephone follow-up, but no differences from the 12-month follow-up were noted.¹

Continue to: WHAT'S NEW

WHAT’S NEW

Study looked at true patient-oriented ­outcome

Previous studies of treatment options for acute uncomplicated diverticulitis looked at short-term outcomes, or at readmission, recurrence, and surgical intervention rate or requirement for percutaneous drainage.^7,8 This study is the first to look at functional return to work (a true patient-oriented outcome). And it is the only study to follow up at 24 months to gauge long-term outcomes with observational treatment.

CAVEATS

Can’t generalize to worse cases

It is worth noting that the findings of this study apply only to the mildest form of CT-proven acute diverticulitis (those patients classified as having Hinchey 1a disease) and are not generalizable to patients with more severe forms. Not enough patients with Hinchey 1b acute diverticulitis were enrolled in the study to reach any conclusions about treatment.

Various guidelines issued outside the United States recommend antibiotics for uncomplicated diverticulitis; however, the American Gastroenterological Association (AGA) indicates that antibiotics should be used selectively.^1,9,10 This recommendation was based on an emerging understanding that diverticulitis may be more inflammatory than infectious in nature. The AGA guideline authors acknowledge that their conclusion was based on low-quality evidence.⁹

CHALLENGES TO IMPLEMENTATION

None to speak of

We see no challenges to implementing this recommendation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2018. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2018;67[7]:435-436,438).

ILLUSTRATIVE CASE

A 58-year-old man presents to your office with a 2-day history of moderate (6/10) left lower quadrant pain, mild fever (none currently), 2 episodes of vomiting, no diarrhea, and no relief with over-the-counter medications. You suspect diverticulitis and obtain an abdominal computed tomography (CT) scan, which shows mild, uncomplicated (Hinchey stage 1a) diverticulitis.

How would you treat him?

Diverticulitis is common; about 200,000 people per year are admitted to the hospital because of diverticulitis in the United States.^2,3 Health care providers typically treat diverticular disease with antibiotics and bowel rest.^2,3 While severe forms of diverticulitis often require parenteral antibiotics and/or surgery, practitioners are increasingly managing the condition with oral antibiotics.⁴

One previous randomized control trial (RCT; N=623) found that antibiotic treatment (compared with no antibiotic treatment) for acute uncomplicated diverticulitis did not speed recovery or prevent complications (perforation or abscess formation) or recurrence at 12 months.⁵ The study’s strengths included limiting enrollment to people with CT-proven diverticulitis, using a good randomization and concealment process, and employing intention-to-treat analysis. The study was limited by a lack of a standardized antibiotic regimen across centers, previous diverticulitis diagnoses in 40% of patients, non-uniform follow-up processes to confirm anatomic resolution, and the lack of assessment to confirm resolution.⁵

STUDY SUMMARY

RCT finds that watchful waiting is just as effective as antibiotic Tx

This newer study was a single-blind RCT that compared treatment with antibiotics to observation among 528 adult patients in the Netherlands. Patients were enrolled if they had CT-proven, primary, left-sided, uncomplicated acute diverticulitis (Hinchey stage 1a and 1b).¹ (The Hinchey classification is based on radiologic findings, with 0 for clinical diverticulitis only, 1a for confined pericolic inflammation or phlegmon, and 1b for pericolic or mesocolic abscess.⁶) Exclusion criteria included suspicion of colonic cancer by CT or ultrasound (US), previous CT/US-proven diverticulitis, sepsis, pregnancy, or antibiotic use in the previous 4 weeks.¹

Observational vs antibiotic treatment. Enrolled patients were randomized to receive IV administration of amoxicillin-clavulanate 1200 mg 4 times daily for at least 48 hours followed by 625 mg PO 3 times daily for 10 total days of antibiotic treatment (n=266) or to be observed (n=262). Computerized randomization, with a random varying block size and stratified by Hinchey classification and center, was performed, and allocation was concealed. The investigators were masked to the allocation until all analyses were completed.¹

The primary outcome was the time to functional recovery (resumption of pre-illness work activities) during a 6-month follow-up period. Secondary outcomes included hospital readmission rate; complicated, ongoing, and recurrent diverticulitis; sigmoid resection; other nonsurgical intervention; antibiotic treatment adverse effects; and all-cause mortality.

Continue to: Results

This study is the first to look at functional return to work and the only study to gauge long-term outcomes with observational treatment.

Results. Median recovery time for observational treatment was not inferior to antibiotic treatment (14 days vs 12 days; P=.15; hazard ratio [HR] for functional recovery=0.91; lower limit of 1-sided 95% confidence interval, 0.78). Observation was not inferior to antibiotics for any of the secondary endpoints at 6 and 12 months of follow-up (complicated diverticulitis, 3.8% vs 2.6%, respectively; P=.377), recurrent diverticulitis (3.4% vs 3%; P=.494), readmission (17.6% vs 12%; P=.148), or adverse events (48.5% vs 54.5%; P=.221). Initial hospitalization length of stay was shorter in the observation group (2 vs 3 days; P=.006). The researchers conducted a 24-month telephone follow-up, but no differences from the 12-month follow-up were noted.¹

WHAT’S NEW

A study that looks at a true patient-oriented outcome

Previous studies of treatment options for acute uncomplicated diverticulitis looked at short-term outcomes, or at readmission, recurrence, and surgical intervention rate, or requirement for percutaneous drainage.^7,8 This study is the first one to look at functional return to work (a true patient-oriented outcome). And it is the only study to look out to 24 months to gauge long-term outcomes with observational treatment.

CAVEATS

Can’t generalize findings to patients with worse forms of diverticulitis

It is worth noting that the findings of this study apply only to the mildest form of CT-proven acute diverticulitis (those patients classified as having Hinchey 1a disease), and is not generalizable to patients with more severe forms. Not enough patients with Hinchey 1b acute diverticulitis were enrolled in the study to reach any conclusions about treatment.

Various guidelines issued outside the United States recommend antibiotics for uncomplicated diverticulitis; however, the American Gastroenterological Association (AGA) indicates that antibiotics should be used selectively.^1,9,10 This recommendation was based on an emerging understanding that diverticulitis maybe more inflammatory than infectious in nature. The AGA guideline authors acknowledge that their conclusion was based on low-quality evidence.⁹

Continuet to: CHALLENGES TO IMPLEMENTATION

None to speak of

We see no challenges to implementing this recommendation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 58-year-old man presents to your office with a 2-day history of moderate (6/10) left lower quadrant pain, mild fever (none currently), 2 episodes of vomiting, no diarrhea, and no relief with over-the-counter medications. You suspect diverticulitis and obtain an abdominal computed tomography (CT) scan, which shows mild, uncomplicated (Hinchey stage 1a) diverticulitis.

How would you treat him?

Diverticulitis is common; about 200,000 people per year are admitted to the hospital because of diverticulitis in the United States.^2,3 Health care providers typically treat diverticular disease with antibiotics and bowel rest.^2,3 While severe forms of diverticulitis often require parenteral antibiotics and/or surgery, practitioners are increasingly managing the condition with oral antibiotics.⁴

One previous randomized control trial (RCT; N=623) found that antibiotic treatment (compared with no antibiotic treatment) for acute uncomplicated diverticulitis did not speed recovery or prevent complications (perforation or abscess formation) or recurrence at 12 months.⁵ The study’s strengths included limiting enrollment to people with CT-proven diverticulitis, using a good randomization and concealment process, and employing intention-to-treat analysis. The study was limited by a lack of a standardized antibiotic regimen across centers, previous diverticulitis diagnoses in 40% of patients, non-uniform follow-up processes to confirm anatomic resolution, and the lack of assessment to confirm resolution.⁵

STUDY SUMMARY

RCT finds that watchful waiting is just as effective as antibiotic Tx

This newer study was a single-blind RCT that compared treatment with antibiotics to observation among 528 adult patients in the Netherlands. Patients were enrolled if they had CT-proven, primary, left-sided, uncomplicated acute diverticulitis (Hinchey stage 1a and 1b).¹ (The Hinchey classification is based on radiologic findings, with 0 for clinical diverticulitis only, 1a for confined pericolic inflammation or phlegmon, and 1b for pericolic or mesocolic abscess.⁶) Exclusion criteria included suspicion of colonic cancer by CT or ultrasound (US), previous CT/US-proven diverticulitis, sepsis, pregnancy, or antibiotic use in the previous 4 weeks.¹

Observational vs antibiotic treatment. Enrolled patients were randomized to receive IV administration of amoxicillin-clavulanate 1200 mg 4 times daily for at least 48 hours followed by 625 mg PO 3 times daily for 10 total days of antibiotic treatment (n=266) or to be observed (n=262). Computerized randomization, with a random varying block size and stratified by Hinchey classification and center, was performed, and allocation was concealed. The investigators were masked to the allocation until all analyses were completed.¹

The primary outcome was the time to functional recovery (resumption of pre-illness work activities) during a 6-month follow-up period. Secondary outcomes included hospital readmission rate; complicated, ongoing, and recurrent diverticulitis; sigmoid resection; other nonsurgical intervention; antibiotic treatment adverse effects; and all-cause mortality.

Continue to: Results

This study is the first to look at functional return to work and the only study to gauge long-term outcomes with observational treatment.

Results. Median recovery time for observational treatment was not inferior to antibiotic treatment (14 days vs 12 days; P=.15; hazard ratio [HR] for functional recovery=0.91; lower limit of 1-sided 95% confidence interval, 0.78). Observation was not inferior to antibiotics for any of the secondary endpoints at 6 and 12 months of follow-up (complicated diverticulitis, 3.8% vs 2.6%, respectively; P=.377), recurrent diverticulitis (3.4% vs 3%; P=.494), readmission (17.6% vs 12%; P=.148), or adverse events (48.5% vs 54.5%; P=.221). Initial hospitalization length of stay was shorter in the observation group (2 vs 3 days; P=.006). The researchers conducted a 24-month telephone follow-up, but no differences from the 12-month follow-up were noted.¹

WHAT’S NEW

A study that looks at a true patient-oriented outcome

Previous studies of treatment options for acute uncomplicated diverticulitis looked at short-term outcomes, or at readmission, recurrence, and surgical intervention rate, or requirement for percutaneous drainage.^7,8 This study is the first one to look at functional return to work (a true patient-oriented outcome). And it is the only study to look out to 24 months to gauge long-term outcomes with observational treatment.

CAVEATS

Can’t generalize findings to patients with worse forms of diverticulitis

It is worth noting that the findings of this study apply only to the mildest form of CT-proven acute diverticulitis (those patients classified as having Hinchey 1a disease), and is not generalizable to patients with more severe forms. Not enough patients with Hinchey 1b acute diverticulitis were enrolled in the study to reach any conclusions about treatment.

Various guidelines issued outside the United States recommend antibiotics for uncomplicated diverticulitis; however, the American Gastroenterological Association (AGA) indicates that antibiotics should be used selectively.^1,9,10 This recommendation was based on an emerging understanding that diverticulitis maybe more inflammatory than infectious in nature. The AGA guideline authors acknowledge that their conclusion was based on low-quality evidence.⁹

Continuet to: CHALLENGES TO IMPLEMENTATION

None to speak of

We see no challenges to implementing this recommendation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 58-year-old man presents to your office with a 2-day history of moderate (6/10) left lower quadrant pain, mild fever (none currently), 2 episodes of vomiting, no diarrhea, and no relief with over-the-counter medications. You suspect diverticulitis and obtain an abdominal computed tomography (CT) scan, which shows mild, uncomplicated (Hinchey stage 1a) diverticulitis.

How would you treat him?

Diverticulitis is common; about 200,000 people per year are admitted to the hospital because of diverticulitis in the United States.^2,3 Health care providers typically treat diverticular disease with antibiotics and bowel rest.^2,3 While severe forms of diverticulitis often require parenteral antibiotics and/or surgery, practitioners are increasingly managing the condition with oral antibiotics.⁴

One previous randomized control trial (RCT; N=623) found that antibiotic treatment (compared with no antibiotic treatment) for acute uncomplicated diverticulitis did not speed recovery or prevent complications (perforation or abscess formation) or recurrence at 12 months.⁵ The study’s strengths included limiting enrollment to people with CT-proven diverticulitis, using a good randomization and concealment process, and employing intention-to-treat analysis. The study was limited by a lack of a standardized antibiotic regimen across centers, previous diverticulitis diagnoses in 40% of patients, non-uniform follow-up processes to confirm anatomic resolution, and the lack of assessment to confirm resolution.⁵

STUDY SUMMARY

RCT finds that watchful waiting is just as effective as antibiotic Tx

This newer study was a single-blind RCT that compared treatment with antibiotics to observation among 528 adult patients in the Netherlands. Patients were enrolled if they had CT-proven, primary, left-sided, uncomplicated acute diverticulitis (Hinchey stage 1a and 1b).¹ (The Hinchey classification is based on radiologic findings, with 0 for clinical diverticulitis only, 1a for confined pericolic inflammation or phlegmon, and 1b for pericolic or mesocolic abscess.⁶) Exclusion criteria included suspicion of colonic cancer by CT or ultrasound (US), previous CT/US-proven diverticulitis, sepsis, pregnancy, or antibiotic use in the previous 4 weeks.¹

Observational vs antibiotic treatment. Enrolled patients were randomized to receive IV administration of amoxicillin-clavulanate 1200 mg 4 times daily for at least 48 hours followed by 625 mg PO 3 times daily for 10 total days of antibiotic treatment (n=266) or to be observed (n=262). Computerized randomization, with a random varying block size and stratified by Hinchey classification and center, was performed, and allocation was concealed. The investigators were masked to the allocation until all analyses were completed.¹

The primary outcome was the time to functional recovery (resumption of pre-illness work activities) during a 6-month follow-up period. Secondary outcomes included hospital readmission rate; complicated, ongoing, and recurrent diverticulitis; sigmoid resection; other nonsurgical intervention; antibiotic treatment adverse effects; and all-cause mortality.

Continue to: Results

This study is the first to look at functional return to work and the only study to gauge long-term outcomes with observational treatment.

Results. Median recovery time for observational treatment was not inferior to antibiotic treatment (14 days vs 12 days; P=.15; hazard ratio [HR] for functional recovery=0.91; lower limit of 1-sided 95% confidence interval, 0.78). Observation was not inferior to antibiotics for any of the secondary endpoints at 6 and 12 months of follow-up (complicated diverticulitis, 3.8% vs 2.6%, respectively; P=.377), recurrent diverticulitis (3.4% vs 3%; P=.494), readmission (17.6% vs 12%; P=.148), or adverse events (48.5% vs 54.5%; P=.221). Initial hospitalization length of stay was shorter in the observation group (2 vs 3 days; P=.006). The researchers conducted a 24-month telephone follow-up, but no differences from the 12-month follow-up were noted.¹

WHAT’S NEW

A study that looks at a true patient-oriented outcome

Previous studies of treatment options for acute uncomplicated diverticulitis looked at short-term outcomes, or at readmission, recurrence, and surgical intervention rate, or requirement for percutaneous drainage.^7,8 This study is the first one to look at functional return to work (a true patient-oriented outcome). And it is the only study to look out to 24 months to gauge long-term outcomes with observational treatment.

CAVEATS

Can’t generalize findings to patients with worse forms of diverticulitis

It is worth noting that the findings of this study apply only to the mildest form of CT-proven acute diverticulitis (those patients classified as having Hinchey 1a disease), and is not generalizable to patients with more severe forms. Not enough patients with Hinchey 1b acute diverticulitis were enrolled in the study to reach any conclusions about treatment.

Various guidelines issued outside the United States recommend antibiotics for uncomplicated diverticulitis; however, the American Gastroenterological Association (AGA) indicates that antibiotics should be used selectively.^1,9,10 This recommendation was based on an emerging understanding that diverticulitis maybe more inflammatory than infectious in nature. The AGA guideline authors acknowledge that their conclusion was based on low-quality evidence.⁹

Continuet to: CHALLENGES TO IMPLEMENTATION

None to speak of

We see no challenges to implementing this recommendation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.